EP1072270B1 - Toxine de Botulinum pour le traitement de la dystonie - Google Patents

Toxine de Botulinum pour le traitement de la dystonie Download PDF

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Publication number
EP1072270B1
EP1072270B1 EP00203294A EP00203294A EP1072270B1 EP 1072270 B1 EP1072270 B1 EP 1072270B1 EP 00203294 A EP00203294 A EP 00203294A EP 00203294 A EP00203294 A EP 00203294A EP 1072270 B1 EP1072270 B1 EP 1072270B1
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Prior art keywords
botulinum
dystonia
botulinum toxin
medicament
type
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EP00203294A
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German (de)
English (en)
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EP1072270A3 (fr
EP1072270A2 (fr
Inventor
K. Roger Aoki
Michael W. Grayston
Steven R. Carlson
Judith M. Leon
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Allergan Inc
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Allergan Inc
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Application filed by Allergan Inc filed Critical Allergan Inc
Priority to EP07002714A priority Critical patent/EP1790352B1/fr
Priority to EP01118792A priority patent/EP1147775B1/fr
Priority to EP01118793A priority patent/EP1147776B1/fr
Priority to EP05017284A priority patent/EP1602379A1/fr
Publication of EP1072270A2 publication Critical patent/EP1072270A2/fr
Publication of EP1072270A3 publication Critical patent/EP1072270A3/fr
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
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    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention provides treatments for dystonia using botulinum toxin type B.
  • Botulinum toxins in particular Botulinum toxin type A, has been used in the treatment of a number of neuromuscular disorders and conditions involving muscular spasm; for example, strabismus, blepharospasm, spasmodic torticollis (cervical dystonia), oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia).
  • the toxin binds rapidly and strongly to presynaptic cholinergic nerve terminals and inhibits the exocytosis of acetylcholine by decreasing the frequency of acetylcholine release. This results in local paralysis and hence relaxation of the muscle afflicted by spasm.
  • Botulinum toxin is a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct neurotoxins have been identified. These have been given the designations A, B, C, D, E, F and G.
  • Botulinum toxin is a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct neurotoxins have been identified. These have been given the designations A, B, C, D, E, F and G.
  • the neurotoxic component of Botulinum toxin has a molecular weight of about 150 kilodaltons and is thought to comprise a short polypeptide chain of about 50 kD which is considered to be responsible for the toxic properties of the toxin, i.e., by interfering with the exocytosis of acetylcholine, by decreasing the frequency of acetylcholine release, and a larger polypeptide chain of about 100 kD which is believed to be necessary to enable the toxin to bind to the presynaptic membrane.
  • the “short” and “long” chains are linked together by means of a simple disulfide bridge.
  • certain serotypes of Botulinum toxin e.g., type E
  • the single chain form is less active but may be converted to the corresponding dichain by nicking with a protease, e.g., trypsin. Both the single and the dichain are useful in the method of the present invention.
  • C. botulinum In general, four physiologic groups of C. botulinum are recognized (I, II, III, IV).
  • the organisms capable of producing a serologically distinct toxin may come from more than one physiological group.
  • Type B and F toxins can be produced by strains from Group I or II.
  • other strains of clostridial species C. baratii, type F; C. butyricum, type E; C. novyi, type C 1 or D
  • C. baratii, type F; C. butyricum, type E; C. novyi, type C 1 or D have been identified which can produce botulinum neurotoxins.
  • Immunotoxin conjugates of ricin and antibodies which are characterized as having enhanced cytotoxicity through improving cell surface affinity, are disclosed in European Patent Specification 0 129 434.
  • the inventors note that botulinum toxin may be utilized in place of ricin.
  • Botulinum toxin is obtained commercially by establishing and growing cultures of C. botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known techniques.
  • Botulinum toxin type A the toxin type generally utilized in treating neuromuscular conditions, is currently available commercially from several sources; for example, from Porton Products Ltd. UK, under the trade name "DYSPORT,” and from Allergan, Inc., Irvine, California, under the trade name BOTOX®.
  • Each serotype of Botulinum toxin has been identified as immunologically different proteins through the use of specific antibodies. For example, if the antibody (antitoxin) recognizes, that is, neutralizes the biological activity of, for example, type A it will not recognize types B, C, D, E, F or G.
  • Botulinum toxins appear to be zinc endopeptidases
  • the mechanism of action of different serotypes, for example, A and E within the neuron appear to be different than that of Type B.
  • the neuronal surface "receptor" for the toxin appears to be different for the serotypes.
  • Botulinum toxins in accordance with the present invention with regard to organ systems which involve the release of neurotransmitter, it is expected to introduce the toxins B, directly by local injections.
  • the Botulinum toxin used according to the present invention is Botulinum toxin type B.
  • Clostridium botulinum types are listed in Table I. Physiologic Groups or Clostridium botulinum Group Toxin Sero-Type Biochemistry Milk Digest Glucose Fermentation Lipase Phages & Plasmids Phenotypically Related Clostridium (nontoxigenic) I A,B,F proteolytic saccharolytic + + + + C. sporogenes II B,E,F nonproteolytic saccharolytic psychotropic - + + + III C,D nonproteolytic saccharolytic + + + + + C. novyi IV G proteolytic nonsaccharolytic + - - - C.
  • toxin types may be produced by selection from the appropriate physiologic group of Clostridium botulinum organisms.
  • the organisms designated as Group I are usually referred to as proteolytic and produce Botulinum toxins of types A, B and F.
  • the organisms designated as Group II are saccharolytic and produce Botulinum toxins of types B, E and F.
  • the organisms designated as Group III produce only Botulinum toxin types C and D and are distinguished from organisms of Groups I and II by the production of significant amounts of propionic acid.
  • Group IV organisms only produce neurotoxin of type G.
  • Botulinum toxin types A, B, C, D, E, F and G are described in Chapter 1 of Botulinum Neurotoxin and Tetanus Toxin, cited above, and/or the references cited therein.
  • Botulinum toxins types B, C, D, E, F and G are also available from various species of clostridia.
  • Organisms which produce Botulinum toxins have been isolated from botulism outbreaks in humans (types A, B, E and F) and animals (types C and D). Their identities were described through the use of specific antitoxins (antibodies) developed against the earlier toxins.
  • Type G toxin was found in soil and has low toxigenicity. However, it has been isolated from autopsy specimens, but thus far there has not been adequate evidence that type G botulism has occurred in humans.
  • the toxin is administered by means of intramuscular injection directly into a local area such as a spastic muscle, preferably in the region of the neuromuscular junction, although alternative types of administration (e.g., subcutaneous injection), which can deliver the toxin directly to the affected region, may be employed where appropriate.
  • the toxin can be presented as a sterile pyrogen-free aqueous solution or dispersion and as a sterile powder for reconstitution into a sterile solution or dispersion.
  • tonicity adjusting agents such as sodium chloride, glycerol and various sugars can be added.
  • Stabilizers such as human serum albumin may also be included.
  • the formulation may be preserved by means of a suitable pharmaceutically acceptable preservative such as a paraben, although preferably it is unpreserved.
  • the toxin is formulated in unit dosage form; for example, it can be provided as a sterile solution in a vial or as a vial or sachet containing a lyophilized powder for reconstituting a suitable vehicle such as saline for injection.
  • the Botulinum toxin is formulated in a solution containing saline and pasteurized human serum albumin, which stabilizes the toxin and minimizes loss through non-specific adsorption.
  • the solution is sterile filtered (0.2 micron filter), filled into individual vials and then vacuum-dried to give a sterile lyophilized powder.
  • the powder can be reconstituted by the addition of sterile unpreserved normal saline (sodium chloride 0.9% for injection).
  • the dose of toxin administered to the patient will depend upon the severity of the condition; e.g., the number of muscle groups requiring treatment, the age and size of the patient and the potency of the toxin.
  • the potency of the toxin is expressed as a multiple of the LD 50 value for the mouse, one unit (U) of toxin being defined as being the equivalent amount of toxin that kills 50% of a group of 18 to 20 female Swiss-Webster mice, weighing about 20 grams each.
  • the dosages used in human therapeutic applications are roughly proportional to the mass of muscle being injected.
  • the dose administered to the patient may be up from about 0.01 to about 1,000 units; for example, up to about 500 units, and preferably in the range from about 80 to about 460 units per patient per treatment, although smaller of larger doses may be administered in appropriate circumstances such as up to about 50 units for the relief of pain and in controlling cholinergic secretions.
  • each patient is injected with a sterile solution containing the confirmation of Botulinum toxin.
  • Total patient doses range from about 0.01 units to 460 units.
  • the aim being to inject the area with the highest concentration of neuromuscular junctions, if known.
  • the position of the needle in the muscle is confirmed by putting the muscle through its range of motion and observing the resultant motion of the needle end.
  • General anaesthesia, local anaesthesia and sedation are used according to the age of the patient, the number of sites to be injected, and the particular needs of the patient. More than one injection and/or sites of injection may be necessary to achieve the desired result.
  • some injections depending on the muscle to be injected, may require the use of fine, hollow, teflon-coated needles, guided by electromyography.
  • an antipsychotic drug such as Thorazine or Haldol
  • 150 units of Botulinum toxin type B by direct injection of such toxin into the facial muscles.
  • the symptoms of tardive dyskinesia i.e., orofacial dyskinesia, athetosis, dystonia, chorea, tics and facial grimacing, etc. are markedly reduced.
  • Botulinum toxin Type B in the Treatment of Spasmodic Torticollis
  • a patient suffering from spasmodic torticollis, as manifested by spasmodic or tonic contractions of the neck musculature, producing stereotyped abnormal deviations of the head, the chin being rotated to one side, and the shoulder being elevated toward the side at which the head is rotated, is treated by injection with 100-1,000 units of Botulinum toxin type B. After 3-7 days, the symptoms are substantially alleviated; i.e., the patient is able to hold his head and shoulder in a normal position.

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Claims (6)

  1. Utilisation de la toxine botulinique de type B pour la fabrication d'un médicament destinée à traiter. la dystonie, à condition que :
    i) le médicament ne soit pas une préparation séchée et congelée comprenant la neurotoxine de C. botulinum de type B associée à des protéines stabilisantes dérivées botulinique afin de former un complexe, le complexe ayant un poids moléculaire déterminé par chromatographie par perméation de gel d'au moins 300 kD, en mélange avec un excipient pharmaceutiquement acceptable pour maintenir la stabilité du complexe à des concentrations de 104 unités LD50 chez la souris par millilitre ou moins, qui quand elle est reconstituée en solution aqueuse conserve au moins 75 % de son activité toxique, destiné au traitement du torticolis spasmodique, de la dysphonie spastique, du blépharospasme et des dystonies régionales des mains ;
    ii) le médicament ne soit pas une combinaison de toxines botuliniques de type A et B destinée au traitement de la dyskinésie tardive, du tremblement essentiel, de la dysphonie spastique ou du blépharospasme ; et
    iii) le médicament ne soit pas destiné à traiter la dyskinésie tardive consécutive à un traitement par la toxine botulinique de type A ou le torticolis spasmodique consécutif à un traitement par le botulinum de type E.
  2. Utilisation selon la revendication 1 dans laquelle la dystonie est une dyskinésie tardive.
  3. Utilisation selon la revendication 1 dans laquelle la dystonie est un torticolis spasmodique.
  4. Utilisation selon la revendication 1 dans laquelle la dystonie est un tremblement essentiel.
  5. Utilisation selon la revendication 1 dans laquelle la dystonie est une dysphonie spastique.
  6. Utilisation selon l'un quelconque des revendications précédentes dans laquelle le médicament est destiné à une administration par injection intramusculaire.
EP00203294A 1993-12-28 1994-12-16 Toxine de Botulinum pour le traitement de la dystonie Expired - Lifetime EP1072270B1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP07002714A EP1790352B1 (fr) 1993-12-28 1994-12-16 Utilisation de la toxine botulique pour la fabrication d'un médicament destiné à réduire la douleur dorsale
EP01118792A EP1147775B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament à réduire la douleur liée à des troubles musculaires
EP01118793A EP1147776B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament pour la traitement des spasmes musculaires
EP05017284A EP1602379A1 (fr) 1993-12-28 1994-12-16 Toxines de Botulinum B pour le traitement du muscle spastique

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US17399693A 1993-12-28 1993-12-28
US173996 1993-12-28
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EP01118792A Division EP1147775B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament à réduire la douleur liée à des troubles musculaires
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EP04019048A Revoked EP1488803B1 (fr) 1993-12-28 1994-12-16 Composante neurotoxique de la toxine botulinique pour la traitement de la dystonie cervicale
EP04000166A Expired - Lifetime EP1421948B1 (fr) 1993-12-28 1994-12-16 Utilisation de toxines botuliniques contre la transpiration chez l'homme
EP05018367A Expired - Lifetime EP1600163B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour traiter un spasme musculaire
EP01118792A Expired - Lifetime EP1147775B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament à réduire la douleur liée à des troubles musculaires
EP05017284A Withdrawn EP1602379A1 (fr) 1993-12-28 1994-12-16 Toxines de Botulinum B pour le traitement du muscle spastique
EP97200028A Expired - Lifetime EP0770395B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine de botulinum pour soulager les maux de tête
EP07002714A Expired - Lifetime EP1790352B1 (fr) 1993-12-28 1994-12-16 Utilisation de la toxine botulique pour la fabrication d'un médicament destiné à réduire la douleur dorsale
EP04018914A Withdrawn EP1486214A1 (fr) 1993-12-28 1994-12-16 Toxine botulinique pour le traitement des spasmes musculaires
EP99203735A Expired - Lifetime EP1010431B2 (fr) 1993-12-28 1994-12-16 Toxines botuliniques A pour le traitement de la douleur liée à des spasmes des muscles lisses
EP01118793A Expired - Lifetime EP1147776B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament pour la traitement des spasmes musculaires
EP00203421A Revoked EP1103267B1 (fr) 1993-12-28 1994-12-16 Toxines botuliniques utilisées dans le traitement de douleurs associées à des maladies musculaires
EP04019047A Revoked EP1477183B1 (fr) 1993-12-28 1994-12-16 Composante neurotoxique de la toxine botulinique pour la modulation des secretions controllées par le système cholinergique
EP08017803A Expired - Lifetime EP2027872B1 (fr) 1993-12-28 1994-12-16 Composant neurotoxique d'une toxine botulique pour traiter la dyskinésie tardive
EP03015589A Revoked EP1366770B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour le traitement de la douleur liée à des troubles musculaires
EP99203920A Expired - Lifetime EP1005867B2 (fr) 1993-12-28 1994-12-16 Toxines de botulinum pour la modulation des secretions controlées par le système cholinergique
EP06016208A Expired - Lifetime EP1757325B1 (fr) 1993-12-28 1994-12-16 Utilisation de la toxine botulinique pour traiter les douleurs myofasciales
EP04019046A Expired - Lifetime EP1502600B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour le traitement de maladies liées aux muscles lisses
EP00203294A Expired - Lifetime EP1072270B1 (fr) 1993-12-28 1994-12-16 Toxine de Botulinum pour le traitement de la dystonie
EP05018368A Expired - Lifetime EP1598077B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour traiter un spasme musculaire
EP05016177A Expired - Lifetime EP1591129B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour le traitement de la douleur liée à la dystonie cervicale
EP95906674A Expired - Lifetime EP0737074B1 (fr) 1993-12-28 1994-12-16 Toxines botulinum utilisees dans le traitement de l'hyperhydrosis
EP03015590A Revoked EP1366771B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour traiter les spasmes musculaires
EP05006665.3A Expired - Lifetime EP1563843B1 (fr) 1993-12-28 1994-12-16 Toxines botuliniques utilisées dans le traitement de maladies musculaires

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EP04019048A Revoked EP1488803B1 (fr) 1993-12-28 1994-12-16 Composante neurotoxique de la toxine botulinique pour la traitement de la dystonie cervicale
EP04000166A Expired - Lifetime EP1421948B1 (fr) 1993-12-28 1994-12-16 Utilisation de toxines botuliniques contre la transpiration chez l'homme
EP05018367A Expired - Lifetime EP1600163B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour traiter un spasme musculaire
EP01118792A Expired - Lifetime EP1147775B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament à réduire la douleur liée à des troubles musculaires
EP05017284A Withdrawn EP1602379A1 (fr) 1993-12-28 1994-12-16 Toxines de Botulinum B pour le traitement du muscle spastique
EP97200028A Expired - Lifetime EP0770395B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine de botulinum pour soulager les maux de tête
EP07002714A Expired - Lifetime EP1790352B1 (fr) 1993-12-28 1994-12-16 Utilisation de la toxine botulique pour la fabrication d'un médicament destiné à réduire la douleur dorsale
EP04018914A Withdrawn EP1486214A1 (fr) 1993-12-28 1994-12-16 Toxine botulinique pour le traitement des spasmes musculaires
EP99203735A Expired - Lifetime EP1010431B2 (fr) 1993-12-28 1994-12-16 Toxines botuliniques A pour le traitement de la douleur liée à des spasmes des muscles lisses
EP01118793A Expired - Lifetime EP1147776B1 (fr) 1993-12-28 1994-12-16 L'utilisation de la toxine botulinique type B pour la préparation d'un médicament pour la traitement des spasmes musculaires
EP00203421A Revoked EP1103267B1 (fr) 1993-12-28 1994-12-16 Toxines botuliniques utilisées dans le traitement de douleurs associées à des maladies musculaires
EP04019047A Revoked EP1477183B1 (fr) 1993-12-28 1994-12-16 Composante neurotoxique de la toxine botulinique pour la modulation des secretions controllées par le système cholinergique
EP08017803A Expired - Lifetime EP2027872B1 (fr) 1993-12-28 1994-12-16 Composant neurotoxique d'une toxine botulique pour traiter la dyskinésie tardive
EP03015589A Revoked EP1366770B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour le traitement de la douleur liée à des troubles musculaires
EP99203920A Expired - Lifetime EP1005867B2 (fr) 1993-12-28 1994-12-16 Toxines de botulinum pour la modulation des secretions controlées par le système cholinergique
EP06016208A Expired - Lifetime EP1757325B1 (fr) 1993-12-28 1994-12-16 Utilisation de la toxine botulinique pour traiter les douleurs myofasciales
EP04019046A Expired - Lifetime EP1502600B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour le traitement de maladies liées aux muscles lisses

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EP05018368A Expired - Lifetime EP1598077B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour traiter un spasme musculaire
EP05016177A Expired - Lifetime EP1591129B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour le traitement de la douleur liée à la dystonie cervicale
EP95906674A Expired - Lifetime EP0737074B1 (fr) 1993-12-28 1994-12-16 Toxines botulinum utilisees dans le traitement de l'hyperhydrosis
EP03015590A Revoked EP1366771B1 (fr) 1993-12-28 1994-12-16 Utilisation du composant neurotoxique de la toxine botulinique pour traiter les spasmes musculaires
EP05006665.3A Expired - Lifetime EP1563843B1 (fr) 1993-12-28 1994-12-16 Toxines botuliniques utilisées dans le traitement de maladies musculaires

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AU (1) AU688452B2 (fr)
CA (2) CA2682117A1 (fr)
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ES (18) ES2247575T3 (fr)
FR (1) FR08C0034I1 (fr)
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DE122009000038I1 (de) 2009-11-05
EP1147775A3 (fr) 2003-01-15
JP2006160753A (ja) 2006-06-22
EP1147775A2 (fr) 2001-10-24
DE69434610T2 (de) 2008-11-27
DE69435249D1 (de) 2009-12-17
DE69434319T3 (de) 2011-02-17
DE69434008D1 (de) 2004-10-21
JP2008056682A (ja) 2008-03-13
DE69434535D1 (de) 2005-12-08
ES2246800T3 (es) 2006-03-01
EP1477183B1 (fr) 2005-11-02
DE69435270D1 (de) 2010-04-01
EP1010431A2 (fr) 2000-06-21
ES2339865T3 (es) 2010-05-26
DE69433394T2 (de) 2004-10-14
EP1421948B1 (fr) 2008-10-08
EP0770395B1 (fr) 2001-10-24
EP1005867B1 (fr) 2003-12-03
EP1366771B1 (fr) 2008-03-26
DE69435330D1 (de) 2011-01-27
HK1070831A1 (en) 2005-06-30
JP2006160754A (ja) 2006-06-22
EP1591129A2 (fr) 2005-11-02
EP1600163B1 (fr) 2010-02-17
ES2355491T3 (es) 2011-03-28
DE122008000042I1 (de) 2009-01-02
JP2002114706A (ja) 2002-04-16
AU688452B2 (en) 1998-03-12
DE69435321D1 (de) 2010-12-16
ES2309973T3 (es) 2008-12-16
ES2207910T3 (es) 2004-06-01
JP2012167116A (ja) 2012-09-06
JP2010202661A (ja) 2010-09-16
ES2163090T3 (es) 2002-01-16
WO1995017904A3 (fr) 1995-10-19
ES2223393T3 (es) 2005-03-01
EP1072270A3 (fr) 2002-08-07
HK1064599A1 (en) 2005-02-04
HK1033274A1 (en) 2001-08-24
EP1005867A2 (fr) 2000-06-07
EP1366770B1 (fr) 2005-07-27
DE69434443T2 (de) 2006-05-24
EP1563843B1 (fr) 2013-08-07
EP1488803B1 (fr) 2008-03-26
EP1488803A1 (fr) 2004-12-22
EP1563843A1 (fr) 2005-08-17
JP2002097156A (ja) 2002-04-02
ES2207910T5 (es) 2010-05-21
JP2010202659A (ja) 2010-09-16
DE69434511D1 (de) 2006-03-02
EP1502600B1 (fr) 2009-10-07
EP1103267B1 (fr) 2004-09-15
DE69435302D1 (de) 2010-08-26
JP2012188433A (ja) 2012-10-04
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JP2012167117A (ja) 2012-09-06
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JP2002087984A (ja) 2002-03-27
DE69435276D1 (de) 2010-04-08
EP1600163A1 (fr) 2005-11-30
HK1071071A1 (en) 2005-07-08
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EP0737074A1 (fr) 1996-10-16
JPH09507234A (ja) 1997-07-22
CA2180011C (fr) 2001-05-15
DE69427869D1 (de) 2001-09-06
DE69434008T2 (de) 2005-09-22
DE69427869T2 (de) 2002-04-11
AU1516295A (en) 1995-07-17
EP1366771A2 (fr) 2003-12-03
JP2002097145A (ja) 2002-04-02
JP2008056683A (ja) 2008-03-13
EP1010431B1 (fr) 2005-03-30
JP2012197287A (ja) 2012-10-18
EP1591129A3 (fr) 2005-11-16
EP1010431A3 (fr) 2001-05-16
EP1147776A3 (fr) 2003-01-15
JP2010209105A (ja) 2010-09-24
EP1591129B1 (fr) 2010-02-24
EP1790352B1 (fr) 2008-07-09
JP3238154B2 (ja) 2001-12-10
EP1598077B1 (fr) 2009-11-04
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JP2013006865A (ja) 2013-01-10
DE69434535T2 (de) 2006-07-20
HK1106700A1 (en) 2008-03-20
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EP1072270A2 (fr) 2001-01-31
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EP1757325A1 (fr) 2007-02-28
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ES2347384T3 (es) 2010-10-28
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JP2008031176A (ja) 2008-02-14
DE69435149D1 (de) 2008-11-20
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ES2334357T3 (es) 2010-03-09
DE69434540T2 (de) 2009-06-18
DE69428813D1 (de) 2001-11-29
EP1366771A3 (fr) 2003-12-10
FR08C0034I1 (fr) 2008-09-26
EP0737074B1 (fr) 2001-08-01
EP1598077A1 (fr) 2005-11-23
EP1421948A3 (fr) 2004-06-16
ES2247575T3 (es) 2006-03-01
ES2251651T3 (es) 2008-07-16
DE69434540D1 (de) 2009-03-26
EP0770395A1 (fr) 1997-05-02
EP1005867B2 (fr) 2010-02-17
EP1486214A1 (fr) 2004-12-15
EP1010431B2 (fr) 2010-07-14
EP1477183A1 (fr) 2004-11-17
CA2682117A1 (fr) 1995-07-06
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JP2010202660A (ja) 2010-09-16
DE69434319D1 (de) 2005-05-04
JP2007262086A (ja) 2007-10-11
ES2248780T3 (es) 2008-06-16
WO1995017904A2 (fr) 1995-07-06
DE69434610D1 (de) 2008-08-21
EP1757325B1 (fr) 2010-11-03
JP2012167115A (ja) 2012-09-06
EP1502600A1 (fr) 2005-02-02
DE69435194D1 (de) 2009-04-16
CA2180011A1 (fr) 1995-07-06
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EP1602379A1 (fr) 2005-12-07
JP2002104991A (ja) 2002-04-10
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EP1790352A1 (fr) 2007-05-30
ES2237033T5 (es) 2010-10-29
EP1005867A3 (fr) 2001-06-13
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JP2006160755A (ja) 2006-06-22
DE69434319T2 (de) 2006-03-09
JP2008063339A (ja) 2008-03-21
ES2242126T3 (es) 2005-11-01
EP1147776A2 (fr) 2001-10-24

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